1. Technical Field
The invention relates to methods and materials involved in identifying Bcl2L12 polypeptide activators and inhibitors. The invention also relates to methods and materials involved in treating cancer.
2. Background Information
Many signaling pathways are involved in cancer initiation, progression, maintenance, and regression. Likewise, signaling pathways are involved in preventing or reducing cancer initiation, progression, and maintenance. In fact, organisms have developed apoptosis and survival signaling pathways to control the fate of cells. Several such pathways have been extensively studied. For example, extensive studies of the apoptosis and survival signaling in neurons and neuroblastoma revealed that survival/cell death regulators such as Bax, Apaf-1, caspase 3, caspase 9, PI3K, Akt, Bcl-2, and Bcl-xL play fundamental roles in neuronal cell death (for review, see, Yuan and Yankner, Nature, 407:802-809 (2000)).
Malignant gliomas represent the most common and most lethal form of brain tumors. The common gliomas involve the cerebral hemispheres of adults and carry a poor prognosis due to their propensity to infiltrate early and diffusely throughout the brain. These diffuse neoplasms are classified histologically as astrocytomas, oligodendrogliomas, or tumors with morphological features of both lineages. The more common astrocytic tumors are subsequently graded as pilocytic astrocytoma, grade I; astrocytoma, grade II; anaplastic astrocytoma, grade III; and glioblastoma multiforme (GBM), grade IV. Grade I tumors are biologically benign and can be surgically cured if deemed resectable at the time of diagnosis. Grade II tumors are well-differentiated malignancies with a long clinical course yet poor surgical outcome due to their diffuse nature and propensity to progress into grade III/IV lesions. The grade III anaplastic astrocytomas are highly aggressive, poorly differentiated, and intensely mitotic lesions that lead to death within a few years. Grade IV GBM tumors possess all of the Grade III histological features and are characterized further by microvascular proliferation and/or necrosis, extreme resistance to extant therapeutic modalities, and neurologically destructive death within 9-12 months.
GBMs can present with one of two distinct clinical histories. GBMs presenting in patients without evidence of prior low-grade disease are considered “primary” or “de novo” GBM. The primary GBMs typically arise in older patients. In contrast, “secondary” GBM usually arise in younger patients who initially present with a low-grade astrocytoma that eventually transforms into a grade IV GBM lesion within 5-10 years of the initial diagnosis, regardless of prior therapy. Indeed, a hallmark feature of the malignant gliomas is their lethal end-point.
On the molecular level, significant effort has been directed towards cataloging the genetic changes present in low- and high-grade gliomas, resulting in the identification of several signature mutations that mark their genesis and malignant evolution. The low-grade gliomas typically harbor PDGF pathway activation as well as p53 loss-of-function mutations; while high-grade disease often exhibits activation/overexpression of EGFR as well as loss of INK4a/ARF and PTEN tumor suppressor gene function. Equally apparent from molecular analysis of the high-grade disease is the fact that many GBMs do not harbor these signature lesions, implying that many other genetic mutations driving glioma progression remain to be identified. In fact, high-grade gliomas typically exhibit a high number of chromosomal structural aberrations that presumably result from compromised genome stability mechanisms. For example, spectral karyotype analyses of GBM samples reveal the presence of many recurrent complex non-reciprocal translocations (NRTs). NRTs are typically the end-product of a repaired double-stranded DNA break (DSB) that can serve as a nidus for amplification or deletion at the breakage site.
Previous cytogenetic and chromosomal comparative genomic hybridization (CGH) studies have uncovered a number of recurrent regional gains and losses in malignant gliomas that appear to convey important clinical information (Mohapatra et al., Genes Chromosomes Cancer, 3:195-206 (1998)). For example, gains of 12q and 19 were found to be more frequent in tumors that were slower to recur, whereas losses of 6q and 13 and gains of 20 were found to be more frequent in tumors that recurred more quickly (Weber et al., Oncogene, 13:983-994 (1996)). In addition, the frequency of 7q and 19 gains differs between relatively radiation-sensitive and radiation-resistant GBMs (Huhn et al., Clin. Cancer Res., 5:1435-43 (1999)).